Journal Club – 24. 03. 08.

Inhibition of temperature-sensitive TRPV3 channel by two natural isochlorogenic acid isomers for alleviation of dermatitis and chronic pruritus

Hang Qia, Yuntao Shib, Han Wua, Canyang Niua, Xiaoying Suna,c,*, KeWei Wanga,c,*

aDepartment of Pharmacology, School of Pharmacy, Qingdao University, Qingdao 266021, China
bState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
cInstitue of Innovative Drugs, Qingdao University, Qingdao 266021, China

Received 22 April 2021; received in revised form 13 July 2021; accepted 30 July 2021

Abstract
Genetic gain-of-function mutations of warm temperature-sensitive transient receptor poten- tial vanilloid 3 (TRPV3) channel cause Olmsted syndrome characterized by severe itching and keratoder- ma, indicating that pharmacological inhibition of TRPV3 may hold promise for therapy of chronic pruritus and skin diseases. However, currently available TRPV3 tool inhibitors are either nonselective or less potent, thus impeding the validation of TRPV3 as therapeutic target. Using whole-cell patch-clamp and single-channel recordings, we report the identification of two natural dicaffeoylquinic acid isomers isochlorogenic acid A (IAA) and isochlorogenic acid B (IAB) that selectively inhibit TRPV3 currents with IC50 values of 2.7  1.3 and 0.9  0.3 mmol/L, respectively, and reduce the channel open probability to 3.7  1.2% and 3.2  1.1% from 26.9  5.5%, respectively. In vivo evaluation confirms that both IAA and IAB significantly reverse the ear swelling of dermatitis and chronic pruritus. Furthermore, the isomer IAB is able to rescue the keratinocyte death induced by TRPV3 agonist carvacrol. Molecular docking combined with site-directed mutations reveals two residues T636 and F666 critical for the binding of the two isomers. Taken together, our identification of isochlorogenic acids A and B that act as specific TRPV3 channel inhibitors and gating modifiers not only provides an essential pharmacological tool for further investigation of the channel pharmacology and pathology, but also holds developmental potential for treatment of dermatitis and chronic pruritus.
2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Abbreviations: 2-APB, 2-aminoethoxydiphenyl borate; AITC, allyl isothiocyanate; DMEM, Dulbecco’s modified Eagle’s medium; HaCaT, human immortalized nontumorigenic keratinocyte; HEK293, human embryonic kidney 293; IAA, isochlorogenic acid A; IAB, isochlorogenic acid B; OS, Olmsted syndrome; RR, ruthenium red; TRP, transient receptor potential.

*Corresponding authors.
E-mail addresses: xiaoyingsun@qdu.edu.cn (Xiaoying Sun), wangkw@qdu.edu.cn (KeWei Wang).

Peer review under responsibility of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.

https://doi.org/10.1016/j.apsb.2021.08.002

2211-3835 a 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).